Neurobiological regulation of extinction learning in appetitve conditioning

当预期的环境刺激不再发生时，抑制行动和反应的能力对灵活、适应性行为至关重要。人们使用厌恶巴甫洛夫条件反射程序对条件反应(CS)和有害的无条件刺激(US)进行了广泛的研究，其中条件刺激(CS)与有害的无条件刺激(US)配对，然后美国被抑制以诱导消失。结果表明，消亡产生了一种新的抑制性记忆，它与最初的学习竞争反应的控制。具体地说，在灭绝过程中形成了一个新的CS-US记忆，它与原始的CS-US记忆竞争以抑制反应。我的研究项目试图了解大脑如何调节消亡记忆的形成和保持。这一研究领域是由一个有影响力的假设形成的，即不同的皮质投射起源于内侧前额叶皮质的下缘亚区，终止于杏仁核或伏隔核壳，分别调节与厌恶或食欲(正)刺激相关的反应的消退。然而，在这一假说的发展过程中，一个被忽视的因素是，使用厌恶刺激的研究是使用巴甫洛夫学习模型进行的，而使用欲望刺激的研究几乎完全是使用工具性条件反射程序进行的。在后者中，操作性反应被食欲刺激所强化，随后被抑制以诱导消亡。鉴于原始记忆是通过不同的学习过程获得的，我们认为可能是学习过程(巴甫洛夫式的或工具性的)，而不是刺激的性质(厌恶或欲望)在消亡期间从下缘皮质招募到不同的投射。我们将使用多学科方法在老鼠身上测试这一新的假设。利用免疫组织化学方法，我们将研究在食欲巴甫洛夫式和工具性条件反射过程中，边缘下投射到伏隔核、壳核或杏仁核基底外侧核的激活情况。使用创新的体内光发生和化学发生策略，我们将剖析这两种投射在食欲工具性条件反射和食欲和厌恶巴甫洛夫条件反射消亡中的作用。这一及时提案的结果将为新的研究奠定基础，这些研究旨在确定明确定义的神经回路中调节食欲条件性反应消退的分子、神经化学和遗传过程。总体而言，这一系列研究将扩大我们对当预期的环境刺激未能发生时，大脑如何调节行为和反应的抑制的理解。

The capacity to inhibit actions and reactions when an anticipated environmental stimulus no longer occurs is critical for flexible, adaptive behaviour. The ensuing decrement in conditioned responding, referred to as extinction, has been extensively researched using aversive Pavlovian conditioning procedures in which a conditional stimulus (CS) is paired with a noxious unconditional stimulus (US), and then the US is withheld to induce extinction. Results suggest that extinction produces a new inhibitory memory that competes with the original learning for control over responding. Specifically, a new CS-no US memory is formed during extinction that competes with the original CS-US memory to suppress responding. My program of research seeks to understand how the brain regulates the formation and retention of extinction memory. This area of research is shaped by the influential hypothesis that distinct cortical projections originating in the infralimbic subregion of the medial prefrontal cortex and terminating in either the amygdala or nucleus accumbens shell mediate the extinction of responding associated with aversive or appetitive (positive) stimuli, respectively. However, a consideration that has been overlooked in the development of this hypothesis is that research using aversive stimuli is conducted using Pavlovian learning models, whereas research using appetitive stimuli has almost exclusively been conducted using instrumental conditioning procedures. In the latter, operant responding is reinforced by an appetitive stimulus, which is subsequently withheld to induce extinction. Given that the original memory is acquired via different learning processes, we propose that it may be the learning process (Pavlovian or instrumental) and not the nature of stimulus (aversive or appetitive) that recruits distinct projections from the infralimbic cortex during extinction. We will use a multidisciplinary approach to test this novel hypothesis in rats. Using immunohistochemistry we will examine the activation of infralimbic projections to the nucleus accumbens shell or basolateral nucleus of the amygdala by extinction in appetitive Pavlovian and instrumental conditioning procedures. Using innovative in vivo optogenetic and chemogenetic strategies we will dissect the roles of these two projections in the extinction of appetitive instrumental conditioning, and appetitive and aversive Pavlovian conditioning. Results from this timely proposal will form the basis for new research aimed at identifying the molecular, neurochemical and genetic processes within well-defined neural circuits that mediate the extinction of appetitive conditioned responding. Overall, this line of research will expand our understanding of how the brain regulates the inhibition of actions and reactions when anticipated environmental stimuli fail to occur.